roleoftnf-alpha,ifn-gamma,andil-10inthedevelopmentof...

Hindawi Publishing CorporationPulmonary MedicineVolume 2012, Article ID 745483, 10 pagesdoi:10.1155/2012/745483

Review Article

Role of TNF-Alpha, IFN-Gamma, and IL-10 in the Development ofPulmonary Tuberculosis

Yone Vila Nova Cavalcanti,1, 2 Maria Carolina Accioly Brelaz,2

Juliana Kelle de Andrade Lemoine Neves,2 Jose Candido Ferraz,3

and Valeria Rego Alves Pereira2

1 Departamento de Biologia, UFRPE, Dom Manoel de Medeiros, S/N, Dois Irmaos, 52171-900 Recife, PE, Brazil2 Departamento de Imunologia, Centro de Pesquisas Aggeu Magalhaes (CPqAM/FIOCRUZ), Avenida Professor Moraes Rego S/N,Cidade Universitaria, Campus da UFPE, 50670-420 Recife, PE, Brazil

3 Nucleo de Educacao Fısica e Ciencias do Esporte, Centro Academico de Vitoria, Universidade Federal de Pernanbuco (UFPE),Vitoria de Santo Antao, PE, Brazil

Correspondence should be addressed to Valeria Rego Alves Pereira, [email protected]

Received 30 August 2012; Revised 31 October 2012; Accepted 5 November 2012

Academic Editor: Jose R. Lapa e Silva

Copyright © 2012 Yone Vila Nova Cavalcanti et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Host immune response against Mycobacterium tuberculosis is mediated by cellular immunity, in which cytokines and Th1 cells playa critical role. In the process of control of the infection by mycobacteria, TNF-alpha seems to have a primordial function. Thiscytokine acts in synergy with IFN-gamma, stimulating the production of reactive nitrogen intermediates (RNIs), thus mediatingthe tuberculostatic function of macrophages, and also stimulating the migration of immune cells to the infection site, contributingto granuloma formation, which controls the disease progression. IFN-gamma is the main cytokine involved in the immuneresponse against mycobacteria, and its major function is the activation of macrophages, allowing them to exert its microbicidalrole functions. Different from TNF-alpha and IFN-gamma, IL-10 is considered primarily an inhibitory cytokine, important toan adequate balance between inflammatory and immunopathologic responses. The increase in IL-10 levels seems to support thesurvival of mycobacteria in the host. Although there is not yet conclusive studies concerning a clear dichotomy between Th1 andTh2 responses, involving protective immunity and susceptibility to the disease, respectively, we can suggest that the knowledgeabout this responses based on the prevailing cytokine profile can help to elucidate the immune response related to the protectionagainst M. tuberculosis.

1. Introduction

The genus Mycobacterium displays more than 100 knownspecies, with a broad geographic distribution, habitat diver-sity, and diverse relations with other organisms, includ-ing more than 20 species presenting different degrees ofpathogenicity to humans [1]. Mycobacterium tuberculosis (M.tuberculosis) (MTB), an intracellular facultative bacillus, isthe most frequent species isolated in human tuberculosis(TB) cases.

Pulmonary tuberculosis is a global public health prob-lem, presenting high incidence in Brazil. It is still the world’sleading cause of death from a single infectious agent. Most

infections are asymptomatic and latent however around5% to 10% of infected people progress to the diseasedevelopment at each year, pulmonary tuberculosis beingfound in most cases. Each second a person is infected withM. tuberculosis in the world. From the lungs, the organism isefficiently transmissible through aerosol. It is estimated that,on average, a person with active TB can infect between 10 and15 individuals per year [2]. The World Health Organization(WHO) works intensively to significantly reduce the TBcases and halve this disease death number until 2015 [3];however, the number of multidrug-resistant TB cases isrising, and this increasingly compromises the disease control[4, 5].

2 Pulmonary Medicine

Latent TB is defined as an infection with M. tuberculosisthat remains within macrophages without replicate, but thatretains the ability to exit latency and cause active diseasewhen there is an interruption of the protective immuneresponse. The reactivation of a latent infection requires theactivation of the quiescent bacilli. Several factors can triggerthe development of active disease from reactivation of latentinfection, which usually involves the decline of the immuneresponse. HIV infection is the most important risk factor forprogression to active disease due to depletion of CD4+ T cells[6]. Advanced age, malnutrition, and medical conditions thatcompromise the immune system are also risk factors for thereactivation [7, 8].

Tuberculosis progression is associated with the immunestatus. It is known that host protective immune responseagainst this pathogen is mediated by cellular immunity,in which certain cytokines and Th1 cells have a criticalrole [9]. Understanding the mechanisms involved in thisresponse, and in particular the function of the cytokinenetwork involved in this disease, is of significant relevance toreach advances in the development of effective control andprevention [10].

2. Cytokines

Cytokines are molecules that mediate mainly the intercellularcommunication in the immune system, being producedby different cell types. Cytokines have pleiotropic andregulatory effects and participate in the host defense and ininflammatory and tissue reparation processes [11].

In tuberculosis, an effective and coordinated partici-pation of different cytokines was already identified, suchas interleukin-12 (IL-12), IL-23, IL-27, IL-18, IL-1, IL-7,and IL-15 [5]. An important aspect associated with theproduction of cytokines in MTB infections is the activationof macrophages in response to IFN-γ and TNF-α signal-ing [12]. Nonactivated macrophages are the usual habitatof MTB, which resists in the intracellular environment,blocking the phagosome fusion with the lysosome, thusavoiding its exposure to low pH and to reactive nitrogenintermediates (RNIs), important to its destruction [12].IFN-γ activated macrophages transpose this blockage andform phagolysosomes expressing RNIs able to eliminateMTB in the infection sites [13]. The cord factor, the19KDa lipoprotein, and other MTB components induce theproduction of IL-12 by macrophages, thereby mobilizing theTh1 cytokine pathway. Figure 1 shows the initial immuneprotection to M. tuberculosis.

Several cytokines, including interleukin IL-12, IL-17,and IL-23, contribute to the host response to mycobacteria,improving the development of Th1 cells [14]. Among Th1cytokines, IFN-γ and TNF-α were identified as the mostimportant agents of the antimycobacterial cytokine cascade.This is due to the formation as well as the maintenanceof the granuloma, which is mediated by TNF-α actingsynergistically with IFN-γ in the activation of macrophagesto produce effector molecules [15].

Recently, a new population of cells was identified andnamed Th17. These cells produce IL-17, IL-21, and IL-22 as

signature cytokines [16, 17]. The IL-17 receptor is expressedin different organs including the liver, lung, and spleen, anddifferent cell types are able to respond to IL-17, such asdendritic cells, macrophages, lymphocytes, epithelial cells,and fibroblasts. The responses induced by the IL-17 geneinclude expression of proinflammatory genes, chemokines,IL-6, IL-8, and antimicrobial proteins. Recent data suggesta superior and more complex role for these cells andtheir cytokines in different intracellular infections, includingbacteria, fungi, and viruses in different mucosal surfaces[18]. Therefore, the balance between protection and Th17cell-mediated pathology is the key in the definition ofconsequences in mucosal infections [19].

Th17 cells also participate in the inflammatory responseat an early mycobacterial infection; however, the productionof IL-17 in the lungs is mainly immunosuppressive of IFN-γ.The protective potential role of Th17 cells during the earlyphase of infection with M. tuberculosis is unknown [20].There are evidences on the role of IL-17 during mycobacterialinfections. Pulmonary infection with BCG or M. tuberculosisstimulated the early secretion of IL-17 from the day 1 to 14and sequentially the development of T cells secreting IFN-γ.Pulmonary infected IL-17 deficient mice with BCG showeda reduction in the delayed hypersensitivity responses, with adeficiency in granuloma formation in the lungs, suggestingthat IL-17 is required for an efficient development of Th1responses [20].

The secretion of IL-23 is essential for the secretion of IL-17, and people with deficiency in the IL-12Rβ1 gene have lowcapacity to produce IL-23, and they have a lower productionof IFN-γ. IL-12 is a cytokine that reduces the expressionof IL-17, and this appears to show a self-regulation oninflammation. The balance between the secretions of IL-23/IL-17 and IL-12/IFN-γ appears to be essential for theregulation of inflammation in response to M. tuberculosis andother mycobacteria [21].

Among the cytokines that are being studied in responseto M. tuberculosis, we can also emphasize interleukin-1.Interleukin-1 is necessary for the control of infection withM. tuberculosis, but the role of its two ligands, IL-1α andIL-1β, and its regulation in vivo are poorly understood. Animportant feature of IL-1 is its control on transcription,arranging the levels of transcription and signal transduction,as evidenced by the variety of immunopathologies andautoinflammatory diseases that occur in the absence of reg-ulation of IL-1 [22, 23]. Little is known about the expressionand processing of IL-1 in the context of infection with M.tuberculosis in vivo. The populations of cells that produce IL-1 during infection have not yet been characterized [24].

Guler et al. [25] investigated the role of IL-1α and IL-1β during chronic infection with M. tuberculosis and spon-taneous reactivation of it in mice. Blockade of IL-1α, but notIL-1β, resulted in increased susceptibility to chronic infectionwith M. tuberculosis. When they neutralized IL-1α or IL-1βalone, they did not observe an increase in the reactivation oflatent tuberculosis. The generation of antibodies neutralizingIL-1α and IL-1β simultaneously did not influence weightgain during reactivation, and they observed a slight increasein the lung bacilli count when compared to the immunized

Pulmonary Medicine 3

NK

IL-12

Cell lysis

Infected

macrophage

Cytotoxic Tlymphocyte

lymphocyte

Antigenpresentation

Activatedmacrophage

Phagocytosis

M. tuberculosis

NK

IL-12

Cell lysis

Infected

macrophage

Antigenpresentat

Activatedmacrophage

Phagocytosis

M.MM tuubbeerrcculosis

CD4+

IFN-γ

IFN-γ

Figure 1: Initial protective response to M. tuberculosis-Th1 profile.

control group. Thus, their results suggested that IL-1α isthe prime mediator of the IL-1RI-dependent and protectiveinnate immune responses to M. tuberculosis in mice.

In a recent study the role of IL-1 in host resistance wasdemonstrated by inducing antibodies against this cytokine,which resulted in an increased mortality during chronicinfection [25].

The granuloma is a typical structure of this disease,where we can find CD4 and CD8 T lymphocytes, B lym-phocytes, macrophages, neutrophils, fibroblasts, and giantmultinucleated cells. IFN-γ-producing CD4 T lymphocytescontribute to the generation of granulomas, besides beingimportant costimulators to the adequate activation of CD8T lymphocytes. The importance of CD4 T lymphocytesfunction is seen in patients with HIV, where the risk of TBincreases with the decrease of the cells counting [26].

Many events mediated by cytokines are important to theestablishment of immunity against MTB and the expressionof host resistance [11].

Response against M. tuberculosis. CD4+ T cells exert regu-latory activity on macrophage function, as well as cytolyticCD8+ lymphocytes. The effector function for the bacterialelimination is mediated by macrophages that are activatedby cytokines derived from T lymphocytes, particularly IFN-γand TNF-α.

3. Tumor Necrosis Factor (TNF-α)

The tumor necrosis factor (TNF, TNF-α) was originallycharacterized as a necrosis inductor in sarcomas in vivo [27].TNF-α is a proinflammatory cytokine which exerts multiplebiological effects. TNF-α expression is strictly controlled,since its superproduction can mediate damaging effectsfound in the septic shock such as arterial hypotension,disseminated vascular coagulation, and lethal hypoglycemia.

In the process of mycobacterial infection control, TNF-αseems to have a primordial role, acting upon a wide variety

of cells. The main producing cells are activated macrophages,T lymphocytes, and dendritic cells [27–29]. This cytokineacts in synergy with IFN-γ, stimulating the production ofreactive nitrogen intermediates (RNIs), thus mediating thetuberculostatic function of macrophages [30, 31]. TNF-αalso stimulates the migration of immune cells to the infectionsite, contributing to the granuloma formation, capable ofcontrolling the disease progression [32].

TNF-α blocking has dramatic effects on the progressionof tuberculosis in experimental models. Neutralization ofTNF-α in murine models results in tuberculosis aggravationor reactivation [32]. The excision of the TNF-α gene or itsreceptor results in deviant granulomas or fulminant acutetuberculosis [33, 34]. Studies have also revealed that TNF-α is expressed in MTB-infected tissues during the wholelatent phase of infection [35], suggesting a contribution, withother cytokines like IFN-γ, in the control of the bacillusmultiplication.

Increased levels of TNF-α are commonly detected inculture supernatants of peripheral blood mononucleatedcells (PBMCs) from patients with pulmonary tuberculosisstimulated with mycobacterial antigens [10, 36, 37]. Moura[38] evaluating the immune response of patients prior to andafter treatment noticed that patients with active pulmonarytuberculosis produced increased levels of TNF-α; howeverthey did not observe significant difference in these cytokinelevels after treatment, concluding that these results reinforcethis cytokine’s role at both the physiopathology and in theprotective immunity of the disease.

A recent study investigated the role played by thenucleotide-binding oligomerization domain-containing pro-tein 2 (NOD2) in the human alveolar macrophage innateresponses and revealed that significant levels of IL-1β,IL-6, and TNF-α were produced after the recognition ofthe ligand with the muramyl dipeptide (MDP). Alveolarmacrophage treatment with MDP has improved the controlof intracellular growth of M. tuberculosis, activity associatedwith a significant production of TNF-α and IL-6 [39].


One of the most overwhelming lines of evidence of theprotective effects of TNF-α is, perhaps, provided by theobservation that patients with rheumatoid arthritis undertreatment with TNF-α antagonists (monoclonal antibodiesagainst TNF-α or TNF-α soluble receptors) have a significantincreased risk of reactivating latent TB [40–42].

On the other hand, there is also evidence showingthat TNF-α may be associated with immunopathologicalresponses in tuberculosis, aforementioned also as the headmediator of the destruction of the pulmonary tissue [43].Elevated levels of TNF-α are related to an excessive inflam-mation with necrosis and cachexy [44, 45].

Tumor necrosis factor (TNF-α) relative roles in MTbhave been a subject of controversy. It was described thatmycobacteria decreases the production of TNF in humanPBMCs, skill which probably contributes to its ability toestablish chronic infections [46]. Produced by macrophages,lymphocytes, neutrophils, and some endothelial cells, TNF-α coordinates the inflammatory response via induction ofother cytokines (IL-1 and IL-6), and the recruitment ofimmune and inflammatory cells through the inductionof chemokine and supraregulation of adhesion molecules.Experimental models have shown that TNF-α plays animportant role not only in host response against M. tubercu-losis but also in the immunopathology of tuberculosis [47].

TNF-α increases the capacity of macrophages to phago-cytose and kill mycobacteria and stimulates apoptosis ofmacrophages, depriving bacilli of host cells and leading todeath and presentation by dendritic cells of mycobacterialantigens [48]. In vivo TNF-α is required for the formationand maintenance of granulomas. Neutralization of TNF-αproduced by mice chronically infected with M. tuberculosisspecific monoclonal antibodies disrupts the integrity ofgranulomas, exacerbates infection, and increases mortality[49].

M. tuberculosis evolved and has developed mechanismswhich interact and modulate the host immune response.Mycobacterium expresses surface antigens that can inducethe production of IL-10 and IL-4, which typically have anti-inflammatory effects [50, 51]. The high expression of IL-4 has been implicated as a virulence factor, both for theanti-inflammatory ability and also for its apparent capacityto promote tissue damage in association with TNF-α [52].These studies suggest that IL-4 (alone or jointly with TNF-α) may play a role in tissue destruction and/or cell deathduring infection by M. tuberculosis. TNF-α is one of themost powerful controlling factors for the recruitment ofmonocytes and is a potent inducer of cell death by apoptosis[53]. Necrosis, on the other hand, is associated with the lysisof the infected cell, the release of feasible M. tuberculosis, anddamage to the surrounding tissues [54]. TNF-α is also a keycytokine involved in this event.

4. Interferon Gamma (IFN-γ)

Interferons (IFNs) are substances originally identified atcellular culture supernatants infected by virus and thatappeared to interfere directly in the viral replication, hence

its denomination [55]. Divided into two major types, typeI IFNs are induced and act effectively in responses againstviruses: IFN-α is secreted mainly by leucocytes, and IFN-β isproduced by fibroblasts. Type II interferon, now referred to asIFN-γ, is synthesized mostly by T lymphocytes and NK cellsafter this cells activation with immune and inflammatorystimuli, rather than viral infection [56]. IFN-γ is the chiefcytokine involved in the protective immune response againstmycobacterial infection. It is produced primarily by CD4and CD8 T lymphocytes and NK cells. It is also known thatnatural killer T cells (NKT) and γδ T lymphocytes, cells witha narrow repertoire of antigen recognition, can also produceIFN-γ in response to mycobacterial stimulation, displayingprotection against M. tuberculosis infection both in vitro andin vivo [12].

The main function of IFN-γ is macrophage activation,rendering them able to exert its microbicidal functions. Itoperates also enhancing the antigen presentation throughthe induction of the expression of molecules from themajor histocompatibility complex (MHC) class I and II andpromoting the differentiation of CD4 T lymphocytes to theTh1 subpopulation [57–59]. IFN-γ induces the transcriptionof more than 200 genes in macrophages, including those forthe production of antimicrobial molecules such as oxygenfree radicals and nitric oxide, which represent one of the besteffector mechanisms for elimination of M. tuberculosis [60].However, some mycobacterial antigens, such as the 19 kDalipoprotein, have the potential to mitigate the response ofmacrophages by blocking the transcription of subsets ofgenes responsive for IFN-γ [61, 62].

A series of clinical and experimental studies have demon-strated the importance of IFN-γ production in the controlof tuberculosis [63–65]. Experiments in mice revealed thatIFN-γ is an essential cytokine for macrophage activation andmycobacteria death in the intracellular environment. Cooperet al. [66] and Flynn et al. [67] have demonstrated that micedeprived from the IFN-γ genes have experienced fulminantinfection by M. tuberculosis.

Individuals with a deficiency in the IFN-γ receptor genehave shown to be extremely susceptible to mycobacterialinfections [68]. The complete deficiency of IFN-γ receptorin humans is associated with increased severity in the courseof infection, poor formation of granulomas, multibacillarylesions, and progressive infection [69]. Studies with individ-uals that presented genetic mutations in the IFN-γ receptorhave also proven that they presented high susceptibility toatypical mycobacterial infections [70].

The interleukin-12 (IL-12)/interferon-γ (IFN-γ) axis isdeterminant to the generation of Th1 lymphocytes, acti-vation of macrophages by T cells, and further eliminationof bacteria. A series of mutations associated to theseaxis components were identified in humans: these includemutation in the IL-12Rβ1, IL-12p40, IFN-γR2 genes, and thesignal transducer and activator of transcription-1 (STAT-1).Most infections associated with these Mendelian disordersarise from the use of BCG or environmental mycobacteria.Nevertheless, some of the disorders are also associated withan increased susceptibility to M. tuberculosis (IFN-γR2 andIL-12p40) [71, 72].


IL-12 enhances IFN-γ production by NK cells andexpands antigen specific Th1 cells. Other cytokines such asIL-23, IL-18, and IL-27 are also important inducers of IFN-γ. About 20 days are enough to produce IFN-γ by Th1lymphocytes, which results in its accumulation in the lungsand bacterial growth arrest [73]. IL-18, a cytokine producedby monocytes, macrophages, and dendritic cells, cooperateswith IL-12 to induce IFN-γ production [61]. Studies clearlyindicate that IL-18 contributes to protect against infection bymycobacteria [74, 75]. Moreover, IL-18 deficient mice wheninfected with M. tuberculosis present reduced levels of IFN-γcompared with normal mice, despite the standard levels ofIL-12 [76].

Morosini and colleagues [77] emphasize through datathat they found in their study the view that in humans,at least at certain stages of pulmonary tuberculosis, thereis a differential compartmentalization of IFN-γ and of theregulatory cytokine IL-12 and IL-10, where the protectionfactor associated with the secretion of IL-12 is present inthe lungs and the component associated with immunosup-pressive IL-10 secretion is predominant in peripheral blood.Furthermore, their results indicate a more critical role forIL-18 in the host response to M. tuberculosis in humans,suggesting that IL-18 may act as a factor for induction ofIFN-γ in the lungs, whereas one can have immunoregulatoryactivity on peripheral circulation [77].

Studies report that patients with less severe formsof pulmonary tuberculosis have a predominance of Th1cytokines such as IFN-γ, whereas the increase in IL-4 levels,a Th2 type cytokine, is related to the disease severity [78,79]. Torres et al. [80] studied the immune response ofpatients’ PBMCs with active tuberculosis and their healthyhousehold contacts in response to the 30-KDa antigen fromM. tuberculosis. Their results demonstrated a defect in theIFN-γ production by patients in response to the investigatedantigen and a strong response to this antigen by the healthycommunicants’ cells, suggesting a protective role of IFN-γ inthose individuals.

After inhalation and subsequent infection with M.tuberculosis in the lungs, dendritic cells infected with thebacilli migrate to the regional lymph node, which occurs,on average, around 14 days after infection, initiating theactivation of T cells [81]. A model study used dendritic cellsinfected with M. tuberculosis inoculated intratracheally in thelung and as a result found that dendritic cells exposed toM. tuberculosis prior to inoculation are better in migratingto the lymph node and in T cell activation [82, 83]. Thesefindings, in association with information about the secretionof cytokines and activation of the populations of CD4+ Tcells, indicate that different subtypes of CD4+ T cells involvedin protection in tuberculosis are activated in the initial phasesof infection and produce cytokines classically consideredimmune protectors such as IL-2, IFN-γ and TNF-α [84, 85].

There is evidence that CD4+ T cells may contribute bothto the control of M. tuberculosis as well as of immunopathol-ogy, contributing to morbidity and mortality in tuberculosisdisease. Reference [86] quantified the variation of IFN-γ/IL-17 in response to specific antigens of M. tuberculosis inpatients with a positive PPD test and healthy individuals and

observed a large variation in the amounts of IL-17 and IFN-γsecreted in response to the various antigens used.

5. Interleukin-10 (IL-10)

Due to its ability to inhibit the T lymphocyte productionof cytokines, IL-10 was originally described as a cytokinesynthesis inhibitory factor (CSIF) [86]. Subsequent studieshave demonstrated that IL-10 could also inhibit Th1 andTh2 subpopulations in vitro [87, 88]. IL-10 acts inhibitingthe production of pro-inflammatory cytokines (IFN-γ, TNF-α and IL-12) and the action of antigen presenting cells,blocking the activation of T lymphocytes through theinhibition of expression of MHC class II molecules [89, 90].Therefore, it has an immunoregulatory function [91].

IL-10 is produced by macrophages and T lymphocytesduring M. tuberculosis infection. Unlike TNF-α and IFN-γ, IL-10 is considered primarily an inhibitory cytokine,important to the adequate balance between inflammatoryand immunopathological responses. However, the increasein IL-10 levels appears to support the mycobacterial survivalin the host. Mice with defective IL-10 exhibit an increasein the antimycobacterial immunity [92]. IL-10 reduces theprotective response to MTB in the CBA mice strain, inwhich IL-10 is produced by phagocytes in the interior of thepulmonary lesion and where a reduction in the TNF and IL-12p40 expression can be observed [93]. IL-10 is also able toinduce the reactivation of tuberculosis in animals [94].

IL-10 is increased in samples obtained from patientswith TB, and a higher capacity of IL-10 production isassociated with an increase in the disease incidence. Inhuman tuberculosis, IL-10 production is higher in aner-gic patients, suggesting that M. tuberculosis induces IL-10production, suppressing an effective immune response [95].Macrophages from patients suffering from tuberculosis aresuppressed in vitro, and the inhibition of IL-10 revertspartially this suppression [90]. In another study, IL-10was capable of directly inhibiting the responses of CD4 Tlymphocyte from donors with latent TB and also reduced theexpression of MHC class I and II, CD40, B7-1, and B7-2 ofmonocytes infected with MTB [96].

Lowering the protective cellular immune response is theM. tuberculosis aim to survive in the host. IL-10 and otherinhibitory mediators of the inflammatory response (TGF-βRII, IL-1Rn e IDO) are detected in the sputum samples ofpatients with TB, whereas 30 days after treatment their leveldecreases considerably, while an increase in the Th1 responseis observed [97].

In some human populations, an increase in IL-10expression was identified, being possible to correlate it withan inefficiency in the BCG (Bacillus Calmette-Guerin) vacci-nation [98]. The analysis of the IL-10 gene polymorphismsinvolved in the development of infectious diseases suggeststhat this polymorphism has a critical role in the immunityand progression of inflammation. The increase in IL-10production can, in particular, suppress the immune responseand promote progression of the disease [99].

Regarding the immunopathogeny of TB, it is unques-tionable the immunosuppressor role presented by IL-10


[100, 101]. Nonetheless, some studies have not detectedincreased levels of this cytokine in PBMCs from patients withactive TB in response to mycobacterial antigens [102].

6. Cytokines in Household TuberculosisContact Cases

The study of household contacts of TB cases is of essentialimportance to the programs for combat and control oftuberculosis, in other words, the epidemiologic surveillanceof household contacts as a means for early diagnosis of TBcases and the decrease of the spread of the disease [103].

Some studies assessed the cytokine profile in groups ofhealthy contacts individuals. From these works, it is impor-tant to mention Demissie [104], who conducted a studycomparing the immune response of infected individuals inthe latent stage with TB patients. The results demonstratedthat TB patients presented a low production of IFN-γ andIL-2 cytokines when compared to individuals with latentinfections. This suggests that the control of TB in thelatent stage is not only associated with increased expressionof Th1 cytokines, but also with the suppression of IL-4activity [104]. Later, the same group [105] compared theexpression of IL-4, IL-4δ2, and IFN-γ in the peripheral bloodof household contacts of TB patients presenting positivesputum. The results demonstrated that the expression of IL-4 was slightly higher in household contacts when comparedto the controls from the community. However, when thehousehold contacts were divided into groups with or withoutimmunological signs of infection with M. tuberculosis, theexpression of IL-4 was clearly elevated in the positive ESAT-6 (signal transducer and activator of transcription 6, anMTB antigen) group and the expression of Th1 cytokinessuch as IFN-γ was low. Thus, they suggest that a strongresponse to the antigen ESAT-6 in individuals exposed to M.tuberculosis correlates with a low expression of IFN-γ andhigher expression of IL-4 and that possibly this profile isassociated with a poor prognosis [105]. The results foundedby our group [106] demonstrated that individuals with orwithout a previous history of tuberculosis and exposed toM. tuberculosis showed a Th1 (TNF-α and IFN-γ) and Th2(IL-10 and TGF-β) profile of cytokines, similar to that foundby Demissie [105], with an IFN-γ production relativelylow when compared to IL-10. These cytokines would beinvolved in shifting the state of latency to the stage of clinicaltuberculosis [106].

The presence of high levels of IL-10 in the plasma ofhousehold contacts was unexpected for the group of [107],since they have also found high levels of IL-10 in the studiedpatients. However, there are few reports in the literature onthe production of IL-10 by household contacts of patientswith tuberculosis [107]. According to [107], these levels aredue to stimulation of mycobacterial antigens that induce thiscytokine production by mononuclear cells. Moreover, we cansuggest that IL-10 was involved in the natural defense thatgoes against excessive proinflammatory responses generatedby TNF-α. Therefore, the simultaneous presence of IL-10 andTNF-α in household communicating TB patients might be

Table 1: Studies of cytokines associated to M. tuberculosis infection.

Cytokine Tuberculosis study References

TNF-αStudies in murine models [32–35, 44]

Studies in patients withpulmonary tuberculosis

[36–39]

IFN-γ

Studies in murine models [45, 66, 67, 76]

Clinical studies[63–65, 77–

80, 85]

Genetic studies [68–72]

IL-10Studies in murine models [92–94]

Studies in patients withtuberculosis

[95–102]

Other cytokines Studies in tuberculosis[14, 16–

21, 24, 25]

beneficial to these individuals [105]. IL-10 may be requiredto modulate proinflammatory effects in patients and inhealthy household tuberculosis individuals.

Table 1 summarizes the main cytokines, associated stud-ies, and references described in this paper.

7. Final Thoughts

The host resistance against infection with M. tuberculosisstarts with the innate immunity, involving the interactionof the bacillus with macrophages and dendritic cells. Littleis known about the transition between the initial control ofinfection and the establishment of latent infection, which islargely due, in part, to the lack of appropriate animal models[108].

Although there are still no conclusive studies about aclear dichotomy between Th1 versus Th2 response, involvingprotective immunity and disease susceptibility, respectively,we can conclude that the knowledge of Th1 and Th2responses helps to elucidate the immune protection profileof the host against M. tuberculosis.

References

[1] D. N. Sato, “Mycobacterium,” in Bacteriologia—um textoilustrado, C. H. P. M. e Silva, Ed., pp. 285–315, Eventos, Riode Janeiro, Brazil, 1999.

[2] WHO, Global Tuberculosis Control, 2011.[3] WHO, The Global Plan Tuberculosis to Stop TB, 2011–2015,

2012.[4] M. Baliza, A. H. Bach, G. L. de Queiroz et al., “High

frequency of resistance to the drugs isoniazid and rifampicinamong tuberculosis cases in the City of Cabo de SantoAgostinho, an urban area in Northeastern Brazil,” Revista daSociedade Brasileira de Medicina Tropical, vol. 41, no. 1, pp.11–16, 2008.

[5] H. Tomioka, Y. Tatano, C. Sano, and T. Shimizu, “Devel-opment of new antituberculous drugs based on bacterialvirulence factors interfering with host cytokine networks,”Journal of Infection and Chemotherapy, vol. 17, no. 3, pp. 302–317, 2011.

[6] E. L. Corbett, C. J. Watt, N. Walker et al., “The growingburden of tuberculosis: global trends and interactions with


the HIV epidemic,” Archives of Internal Medicine, vol. 163,no. 9, pp. 1009–1021, 2003.

[7] T. R. Frieden, T. R. Sterling, S. S. Munsiff, C. J. Watt, and C.Dye, “Tuberculosis,” The Lancet, vol. 362, no. 9387, pp. 887–899, 2003.

[8] K. E. Dooley and R. E. Chaisson, “Tuberculosis and diabetesmellitus: convergence of two epidemics,” The Lancet Infec-tious Diseases, vol. 9, no. 12, pp. 737–746, 2009.

[9] Y. Kinjo, K. Kawakami, K. Uezu et al., “Contribution of IL-18 to Th1 response and host defense against infection byMycobacterium tuberculosis: a comparative study with IL-12p40,” Journal of Immunology, vol. 169, no. 1, pp. 323–329,2002.

[10] C. H. Wang, H. C. Lin, C. Y. Liu et al., “Upregulation ofinducible nitric oxide synthase and cytokine secretion inperipheral blood monocytes from pulmonary tuberculosispatients,” International Journal of Tuberculosis and LungDisease, vol. 5, no. 3, pp. 283–291, 2001.

[11] A. Gupta, A. Kaul, A. G. Tsolaki, U. Kishore, and S. Bhakta,“Mycobacterium tuberculosis: immune evasion, latency andreactivation,” Immunobiology, vol. 217, no. 3, pp. 363–374,2012.

[12] A. M. Cooper and S. A. Khader, “The role of cytokines inthe initiation, expansion, and control of cellular immunityto tuberculosis,” Immunological Reviews, vol. 226, no. 1, pp.191–204, 2008.

[13] S. D. Lawn, L. Myer, D. Edwards, L. G. Bekker, and R. Wood,“Short-term and long-term risk of tuberculosis associatedwith CD4 cell recovery during antiretroviral therapy in SouthAfrica,” AIDS, vol. 23, no. 13, pp. 1717–1725, 2009.

[14] S. A. Khader, G. K. Bell, J. E. Pearl et al., “IL-23 and IL-17 in the establishment of protective pulmonary CD4+ Tcell responses after vaccination and during Mycobacteriumtuberculosis challenge,” Nature Immunology, vol. 8, no. 4, pp.369–377, 2007.

[15] P. G. Lin and J. L. Flynn, “Understanding latent tuberculosis:a moving target,” Journal of Immunology, vol. 185, no. 1, pp.15–22, 2010.

[16] L. E. Harrington, R. D. Hatton, P. R. Mangan et al.,“Interleukin 17-producing CD4+ effector T cells develop viaa lineage distinct from the T helper type 1 and 2 lineages,”Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005.

[17] H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 Tcells regulates tissue inflammation by producing interleukin17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005.

[18] M. Kader, X. Wang, M. Piatak et al., “α4+β7hiCD4+ memoryT cells harbor most Th-17 cells and are preferentially infectedduring acute SIV infection,” Mucosal Immunology, vol. 2, no.5, pp. 439–449, 2009.

[19] E. Torrado and A. M. Cooper, “IL-17 and Th17 cells intuberculosis,” Cytokine and Growth Factor Reviews, vol. 21,no. 6, pp. 455–462, 2010.

[20] T. M. Wozniak, B. M. Saunders, A. A. Ryan, and W. J. Britton,“Mycobacterium bovis BCG-specific Th17 cells confer partialprotection against Mycobacterium tuberculosis infection inthe absence of γ interferon,” Infection and Immunity, vol. 78,no. 10, pp. 4187–4194, 2010.

[21] I. L. D. Moutinho, “Tuberculose: aspectos imunologicos nainfeccao e na doenca,” Revista Medica de Minas Gerais, vol.21, no. 1, pp. 42–48, 2011.

[22] C. A. Dinarello, “Immunological and inflammatory func-tions of the interleukin-1 family,” Annual Review of Immunol-ogy, vol. 27, pp. 519–550, 2009.

[23] C. Garlanda, D. Di Liberto, A. Vecchi et al., “Dampingexcessive inflammation and tissue damage in Mycobacteriumtuberculosis infection by toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling,”Journal of Immunology, vol. 179, no. 5, pp. 3119–3125, 2007.

[24] D. M.-B. Katrin, B. B. Andrade, D. L. Barber et al.,“Innate and adaptive interferons suppress IL-1a and IL-1bproduction by distinct pulmonary myeloid subsets duringMycobacterium tuberculosis infection,” Immunity, vol. 35, no.6, pp. 1023–1034, 2011.

[25] R. Guler, S. P. Parihar, G. Spohn, P. Johansen, F. Brombacher,and M. F. Bachmann, “Blocking IL-1α but not IL-1β increasessusceptibility to chronic Mycobacterium tuberculosis infectionin mice,” Vaccine, vol. 29, no. 6, pp. 1339–1346, 2011.

[26] E. A. Carswell, L. J. Old, Kassel, R. L. Green, N. Fiore, and B.Williamson, “An endotoxin-induced serum factor that causesnecrosis of tumors,” Proceedings of the National Academy ofSciences of the United States of America, vol. 72, no. 9, pp.3666–3670, 1975.

[27] P. F. Barnes, S. Lu, J. S. Abrams, E. Wang, M. Yamamura, andR. L. Modlin, “Cytokine production at the site of disease inhuman tuberculosis,” Infection and Immunity, vol. 61, no. 8,pp. 3482–3489, 1993.

[28] C. H. Ladel, G. Szalay, D. Riedel, and S. H. E. Kaufmann,“Interleukin-12 secretion by Mycobacterium tuberculosis-infected macrophages,” Infection and Immunity, vol. 65, no.5, pp. 1936–1938, 1997.

[29] N. V. Serbina and J. L. Flynn, “Early emergence of CD8+ Tcells primed for production of type 1 cytokines in the lungsof Mycobacterium tuberculosis-infected mice,” Infection andImmunity, vol. 67, no. 8, pp. 3980–3988, 1999.

[30] K. Yu, C. Mitchell, Y. Xing, R. S. Magliozzo, B. R. Bloom,and J. Chan, “Toxicity of nitrogen oxides and related oxidantson mycobacteria: M. tuberculosis is resistant to peroxynitriteanion,” Tubercle and Lung Disease, vol. 79, no. 4, pp. 191–198,1999.

[31] C. A. Scanga, V. P. Mohan, K. Yu et al., “Depletion of CD4+

T cells causes reactivation of murine persistent tuberculosisdespite continued expression of interferon γ and nitric oxidesynthase 2,” Journal of Experimental Medicine, vol. 192, no. 3,pp. 347–358, 2000.

[32] V. P. Mohan, C. A. Scanga, K. Yu et al., “Effects of tumornecrosis factor α on host immune response in chronicpersistent tuberculosis: possible role for limiting pathology,”Infection and Immunity, vol. 69, no. 3, pp. 1847–1855, 2001.

[33] J. L. Flynn, M. M. Goldstein, J. Chan et al., “Tumor necrosisfactor-α is required in the protective immune responseagainst Mycobacterium tuberculosis in mice,” Immunity, vol.2, no. 6, pp. 561–572, 1995.

[34] A. G. D. Bean, D. R. Roach, H. Briscoe et al., “Structural defi-ciencies in granuloma formation in TNF gene-targeted miceunderlie the heightened susceptibility to aerosol Mycobac-terium tuberculosis infection, which is not compensated forby lymphotoxin,” Journal of Immunology, vol. 162, no. 6, pp.3504–3511, 1999.

[35] J. L. Flynn, C. A. Scanga, K. E. Tanaka, and J. Chan, “Effectsof aminoguanidine on latent murine tuberculosis,” Journal ofImmunology, vol. 160, no. 4, pp. 1796–1803, 1998.

[36] D. Dlugovitzky, M. L. Bay, L. Rateni et al., “Influenceof disease severity on nitrite and cytokine production byperipheral blood mononuclear cells (PBMC) from patientswith pulmonary tuberculosis (TB),” Clinical and Experimen-tal Immunology, vol. 122, no. 3, pp. 343–349, 2000.


[37] R. Al-Attiyah, A. El-Shazly, and A. S. Mustafa, “Comparativeanalysis of spontaneous and mycobacterial antigen-inducedsecretion of Th1, Th2 and pro-inflammatory cytokines byperipheral blood mononuclear cells of tuberculosis patients,”Scandinavian Journal of Immunology, vol. 75, no. 6, pp. 623–632, 2012.

[38] E. P. Moura, “Avaliacao da resposta immune cellular ehumoral antes e depois do tratamento da tuberculosepulmonar,” Tese, p. 90, 2002.

[39] E. Juarez, C. Carranza, F. Hernandez-Sanchez et al., “NOD2enhances the innate response of alveolar macrophages toMycobacterium tuberculosis in humans,” European Journal ofImmunology, vol. 42, no. 4, pp. 880–889, 2012.

[40] R. N. Maini, P. C. Taylor, E. Paleolog et al., “Anti-tumournecrosis factor specific antibody (infliximab) treatmentprovides insights into the pathophysiology of rheumatoidarthritis,” Annals of the Rheumatic Diseases, vol. 58, no. 1, pp.I56–I60, 1999.

[41] I. Solovic, M. Sester, J. J. Gomez-Reino et al., “The riskof tuberculosis related to tumour necrosis factor antagonisttherapies: a TBNET consensus statement,” European Respira-tory Journal, vol. 36, no. 5, pp. 1185–1206, 2010.

[42] A. Stallmach, S. Hagel, and T. Bruns, “Adverse effects ofbiologics used for treating IBD,” Best Practice and Research:Clinical Gastroenterology, vol. 24, no. 2, pp. 167–182, 2010.

[43] J. L. Flynn, J. Chan, and P. L. Lin, “Macrophages and controlof granulomatous inflammation in tuberculosis,” MucosalImmunology, vol. 4, no. 3, pp. 271–278, 2011.

[44] L. G. Bekker, A. L. Moreira, A. Bergtold, S. Freeman, B.Ryffel, and G. Kaplan, “Immunopathologic effects of tumornecrosis factor alpha in murine mycobacterial infection aredose dependent,” Infection and Immunity, vol. 68, no. 12, pp.6954–6961, 2000.

[45] S. Ehlers, J. Benini, H. D. Held, C. Roeck, G. Alber, andS. Uhlig, “αβ T cell receptor-positive cells and interferon-γ, but not inducible nitric oxide synthase, are critical forgranuloma necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology,” Journal of Experi-mental Medicine, vol. 194, no. 12, pp. 1847–1859, 2001.

[46] B. Jonsson, M. Ridell, and A. E. Wold, “Phagocyto-sis and cytokine response to rough and smooth colonyvariants of mycobacterium abscessus byhuman peripheralblood mononuclear cells,” Acta Pathologica, Microbiologica etImmunologica Scandinavica. In press.

[47] I. Dambuza, N. Allie, L. Fick et al., “Efficacy of membraneTNF mediated host resistance is dependent on mycobacterialvirulence,” Tuberculosis, vol. 88, no. 3, pp. 221–234, 2008.

[48] J. Keane, H. G. Remold, and H. Kornfeld, “Virulent Mycobac-terium tuberculosis strains evade apoptosis of infected alveo-lar macrophages,” Journal of Immunology, vol. 164, no. 4, pp.2016–2020, 2000.

[49] C. M. Robinson, J. Y. Jung, and G. J. Nau, “Interferon-γ, tumor necrosis factor, and interleukin-18 cooperate tocontrol growth of Mycobacterium tuberculosis in humanmacrophages,” Cytokine, vol. 60, no. 1, pp. 233–241, 2012.

[50] C. Manca, M. B. Reed, S. Freeman et al., “Differentialmonocyte activation underlies strain-specific Mycobacteriumtuberculosis pathogenesis,” Infection and Immunity, vol. 72,no. 9, pp. 5511–5514, 2004.

[51] Y. van Kooyk and T. B. H. Geijtenbeek, “DC-SIGN: escapemechanism for pathogens,” Nature Reviews Immunology, vol.3, no. 9, pp. 697–709, 2003.

[52] G. T. Seah and G. A. W. Rook, “IL-4 influences apoptosisof mycobacterium-reactive lymphocytes in the presence of

TNF-α,” Journal of Immunology, vol. 167, no. 3, pp. 1230–1237, 2001.

[53] S. Stenger, “Immunological control of tuberculosis: role oftumour necrosis factor and more,” Annals of the RheumaticDiseases, vol. 64, supplement 4, pp. iv24–iv28, 2005.

[54] M. Bocchino, D. Galati, A. Sanduzzi, V. Colizzi, E. Brunetti,and G. Mancino, “Role of mycobacteria-induced mono-cyte/macrophage apoptosis in the pathogenesis of humantuberculosis,” International Journal of Tuberculosis and LungDisease, vol. 9, no. 4, pp. 375–383, 2005.

[55] A. Isaacs, J. Lindenmann, and R. C. Valentine, “Virusinterference. II. Some properties of interferon,” Proceedingsof the Royal Society of London, Series B, vol. 1471, no. 927, pp.268–273, 1957.

[56] G. H. Schreiber and R. D. Schereiber, “Interferon-γ,” in TheCytokine Handbook, A. W. Thomson and M. T. Lotze, Eds.,vol. 1, chapter 24, pp. 567–601, Elsevier, New York, NY, USA,4th edition.

[57] I. E. A. Flesch, J. H. Hess, S. Huang et al., “Early interleukin12 production by macrophages in response to mycobacterialinfection depends on interferon γ and tumor necrosis factorα,” Journal of Experimental Medicine, vol. 181, no. 5, pp.1615–1621, 1995.

[58] M. J. Fenton, M. W. Vermeulen, S. Kim, M. Burdick, R. M.Strieter, and H. Kornfeld, “Induction of γ interferon pro-duction in human alveolar macrophages by Mycobacteriumtuberculosis,” Infection and Immunity, vol. 65, no. 12, pp.5149–5156, 1997.

[59] A. Oberholzer, C. Oberholzer, and L. L. Moldawer, “Cytokinesignaling—regulation of the immune response in normaland critically ill states,” Critical Care Medicine, vol. 28, no.4, supplement, pp. N3–N12, 2000.

[60] A. M. Cooper, “Cell-mediated immune responses in tuber-culosis,” Annual Review of Immunology, vol. 27, pp. 393–422,2009.

[61] A. J. Gehring, R. E. Rojas, D. H. Canaday, D. L. Lakey,C. V. Harding, and W. H. Boom, “The Mycobacteriumtuberculosis 19-kilodalton lipoprotein inhibits γ interferon-regulated HLA-DR and FcγR1 on human macrophagesthrough toll-like receptor 2,” Infection and Immunity, vol. 71,no. 8, pp. 4487–4497, 2003.

[62] C. V. Harding, R. K. Pai, M. Convery, T. A. Hamil-ton, and W. Henry Boom, “Inhibition of IFN-γ-inducedclass II transactivator expression by a 19-kDa lipoproteinfrom Mycobacterium tuberculosis: a potential mechanism forimmune evasion,” Journal of Immunology, vol. 171, no. 1, pp.175–184, 2003.

[63] R. C. O. Tavares, J. Salgado, V. B. Moreira et al., “Cell pro-liferation and interferon-γ response to recombinant MBP-3, NarL, MT-10.3, and 16kDa Mycobacterium tuberculosisantigens in Brazilian tuberculosis patients,” Memorias doInstituto Oswaldo Cruz, vol. 101, no. 8, pp. 857–861, 2006.

[64] A. Nienhaus, A. Schablon, and R. Diel, “Interferon-γ releaseassay for the diagnosis of latent TB infection—analysis ofdiscordant results, when compared to the tuberculin skintest,” PLoS ONE, vol. 3, no. 7, Article ID e2665, 2008.

[65] J. C. T. Costa, R. Silva, R. Sa, M. J. Cardoso, C. Ribeiro, andA. Nienhaus, “Comparison of interferon-γ release assay andtuberculin test for screening in healthcare workers,” RevistaPortuguesa de Pneumologia, vol. 16, no. 2, pp. 211–221, 2010.

[66] A. M. Cooper, D. K. Dalton, T. A. Stewart, J. P. Griffin, D.G. Russell, and I. M. Orme, “Disseminated tuberculosis ininterferon γ gene-disrupted mice,” Journal of ExperimentalMedicine, vol. 178, no. 6, pp. 2243–2247, 1993.


[67] J. L. Flynn, J. Chan, K. J. Triebold, D. K. Dalton, T. A.Stewart, and B. R. Bloom, “An essential role for interferon γin resistance to Mycobacterium tuberculosis infection,” Journalof Experimental Medicine, vol. 178, no. 6, pp. 2249–2254,1993.

[68] M. J. Newport, C. M. Huxley, S. Huston et al., “A muta-tion in the interferon-γ-receptor gene and susceptibilityto mycobacterial infection,” The New England Journal ofMedicine, vol. 335, no. 26, pp. 1941–1949, 1996.

[69] T. H. M. Ottenhoff, F. A. W. Verreck, M. A. Hoeve, andE. van de Vosse, “Control of human host immunity tomycobacteria,” Tuberculosis, vol. 85, no. 1-2, pp. 53–64, 2005.

[70] E. Jouanguy, F. Altare, S. Lamhamedi et al., “Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection,” The New England Journal of Medicine, vol.335, no. 26, pp. 1956–1961, 1996.

[71] J. L. Casanova and L. Abel, “Genetic dissection of immunityto mycobacteria: the human model,” Annual Review ofImmunology, vol. 20, pp. 581–620, 2002.

[72] G. S. Cooke and A. V. S. Hill, “Genetics of susceptibility tohuman infectious disease,” Nature Reviews Genetics, vol. 2,no. 12, pp. 967–977, 2001.

[73] H. M. S. Algood, J. Chan, and J. L. Flynn, “Chemokines andtuberculosis,” Cytokine and Growth Factor Reviews, vol. 14,no. 6, pp. 467–477, 2003.

[74] V. E. Garcıa, K. Uyemura, P. A. Sieling et al., “IL-18 promotestype 1 cytokine production from NK cells and T cells inhuman intracellular infection,” Journal of Immunology, vol.162, no. 10, pp. 6114–6121, 1999.

[75] R. Vankayalapati, B. Wizel, S. E. Weis, B. Samten, W. M.Girard, and P. F. Barnes, “Production of interleukin-18 inhuman tuberculosis,” Journal of Infectious Diseases, vol. 182,no. 1, pp. 234–239, 2000.

[76] I. Sugawara, H. Yamada, H. Kaneko, S. Mizuno, K. Takeda,and S. Akira, “Role of interleukin-18 (IL-18) in mycobacterialinfection in IL-18- gene-disrupted mice,” Infection andImmunity, vol. 67, no. 5, pp. 2585–2589, 1999.

[77] M. Morosini, F. Meloni, A. M. Bianco et al., “The assessmentof IFN-γ and its regulatory cytokines in the plasma and bron-choalveolar lavage fluid of patients with active pulmonarytuberculosis,” International Journal of Tuberculosis and LungDisease, vol. 7, no. 10, pp. 994–1000, 2003.

[78] D. Dlugovitzky, A. Torres-Morales, L. Rateni et al., “Cir-culating profile of Th1 and Th2 cytokines in tuberculosispatients with different degrees of pulmonary involvement,”FEMS Immunology and Medical Microbiology, vol. 18, no. 3,pp. 203–207, 1997.

[79] D. Dlugovitzky, M. L. Bay, L. Rateni et al., “In vitro synthesisof interferon-γ, interleukin-4, transforming growth factor-β and interleukin-1β by peripheral blood mononuclear cellsfrom tuberculosis patients: Relationship with the severity ofpulmonary involvement,” Scandinavian Journal of Immunol-ogy, vol. 49, no. 2, pp. 210–217, 1999.

[80] M. Torres, T. Herrera, H. Villareal, E. A. Rich, and E. Sada,“Cytokine profiles for peripheral blood lymphocytes frompatients with active pulmonary tuberculosis and healthyhousehold contacts in response to the 30-kilodalton antigenof Mycobacterium tuberculosis,” Infection and Immunity, vol.66, no. 1, pp. 176–180, 1998.

[81] A. J. Wolf, B. Linas, G. J. Trevejo-Nunez et al., “Mycobac-terium tuberculosis infects dendritic cells with high frequencyand impairs their function in vivo,” Journal of Immunology,vol. 179, no. 4, pp. 2509–2519, 2007.

[82] S. A. Khader, S. Partida-Sanchez, G. Bell et al., “Interleukin12p40 is required for dendritic cell migration and T cellpriming after Mycobacterium tuberculosis infection,” Journalof Experimental Medicine, vol. 203, no. 7, pp. 1805–1815,2006.

[83] C. Demangel, P. Bertolino, and W. J. Britton, “Autocrine IL-10 impairs dendritic cell (DC)-derived immune responsesto mycobacterial infection by suppressing DC trafficking todraining lymph nodes and local IL-12 production,” EuropeanJournal of Immunology, vol. 32, no. 4, pp. 994–1002, 2002.

[84] Y. J. Jung, L. Ryan, R. LaCourse, and R. J. North, “Propertiesand protective value of the secondary versus primary T helpertype 1 response to airborne Mycobacterium tuberculosisinfection in mice,” Journal of Experimental Medicine, vol. 201,no. 12, pp. 1915–1924, 2005.

[85] L. Fan, H. Xiao, Z. Hu, and J. D. Ernst, “Variation ofMycobacterium tuberculosis antigen-specific IFN-c and IL-17 responses in healthy tuberculin skin test (TST)-positivehuman subjects,” PLoS ONE, no. 8, Article ID e42716, 2012.

[86] D. F. Fiorentino, M. W. Bond, and T. R. Mosmann, “Twotypes of mouse T helper cell. IV. Th2 clones secrete a factorthat inhibits cytokine production by Th1 clones,” Journal ofExperimental Medicine, vol. 170, no. 6, pp. 2081–2095, 1989.

[87] R. de Waal Malefyt, H. Yssel, and J. E. de Vries, “Directeffects of IL-10 on subsets of human CD4+ T cell clones andresting T cells: specific inhibition of IL-2 production andproliferation,” Journal of Immunology, vol. 150, no. 11, pp.4754–4765, 1993.

[88] L. Schandene, C. Alonso-Vega, F. Willems et al., “B7/CD28-dependent IL-5 production by human resting T cells isinhibited by IL-10,” Journal of Immunology, vol. 152, no. 9,pp. 4368–4374, 1994.

[89] S. A. Fulton, J. V. Cross, Z. T. Toossi, and W. H. Boom, “Reg-ulation of interleukin-12 by interleukin-10, transforminggrowth factor-β, tumor necrosis factor-α, and interferon-γ inhuman monocytes infected with Mycobacterium tuberculosisH37Ra,” Journal of Infectious Diseases, vol. 178, no. 4, pp.1105–1114, 1998.

[90] J. L. Flynn and J. Chan, “Immunology of tuberculsis,” AnnualReview of Immunology, vol. 19, pp. 93–129, 2001.

[91] A. D’Andrea, M. Aste-Amezaga, N. M. Valiante, X. Ma, M.Kubin, and G. Trinchieri, “Interleukin 10 (IL-10) inhibitshuman lymphocyte interferon γ-production by suppressingnatural killer cell stimulatory factor/IL-12 synthesis in acces-sory cells,” Journal of Experimental Medicine, vol. 178, no. 3,pp. 1041–1048, 1993.

[92] P. J. Murray and R. A. Young, “Increased antimycobacterialimmunity in interleukin-10-deficient mice,” Infection andImmunity, vol. 67, no. 6, pp. 3087–3095, 1999.

[93] G. L. Beamer, D. K. Flaherty, B. D. Assogba et al.,“Interleukin-10 promotes Mycobacterium tuberculosis diseaseprogression in CBA/J mice,” Journal of Immunology, vol. 181,no. 8, pp. 5545–5550, 2008.

[94] M. I. Henao, C. Montes, S. C. Parıs, and L. F. Garcıa,“Cytokine gene polymorphisms in Colombian patients withdifferent clinical presentations of tuberculosis,” Tuberculosis,vol. 86, no. 1, pp. 11–19, 2006.

[95] V. A. Boussiotis, E. Y. Tsai, E. J. Yunis et al., “IL-10-producingT cells suppress immune responses in anergic tuberculosispatients,” Journal of Clinical Investigation, vol. 105, no. 9, pp.1317–1325, 2000.

[96] R. E. Rojas, K. N. Balaji, A. Subramanian, and W. H. Boom,“Regulation of human CD4+αβ T-cell-receptor-positive


(TCR+) and γδ TCR+ T-cell responses to Mycobacteriumtuberculosis by interleukin-10 and transforming growthfactor β,” Infection and Immunity, vol. 67, no. 12, pp. 6461–6472, 1999.

[97] A. S. Almeida, P. M. Lago, N. Boechat et al., “Tuberculosis isassociated with a down-modulatory lung immune responsethat impairs Th1-type immunity,” Journal of Immunology,vol. 183, no. 1, pp. 718–731, 2009.

[98] R. E. Weir, G. F. Black, H. M. Dockrell et al., “Mycobac-terial purified protein derivatives stimulate innate immu-nity: Malawians show enhanced tumor necrosis factor α,interleukin-1β (IL-1β), and IL-10 responses compared tothose of adolescents in the United Kingdom,” Infection andImmunity, vol. 72, no. 3, pp. 1807–1811, 2004.

[99] H. D. Shin, B. L. Park, L. H. Kim, H. S. Cheong, I. H.Lee, and S. K. Park, “Common interleukin 10 polymorphismassociated with decreased risk of tuberculosis,” Experimentaland Molecular Medicine, vol. 37, no. 2, pp. 128–132, 2005.

[100] C. B. Pereira, M. Palaci, O. H. M. Leite, A. J. S. Duarte, andG. Benard, “Monocyte cytokine secretion in patients withpulmonary tuberculosis differs from that of healthy infectedsubjects and correlates with clinical manifestations,” Microbesand Infection, vol. 6, no. 1, pp. 25–33, 2004.

[101] A. A. Awomoyi, A. Marchant, J. M. M. Howson, K. P. W. J.McAdam, J. M. Blackwell, and M. J. Newport, “Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1), andsusceptibility to tuberculosis,” Journal of Infectious Diseases,vol. 186, no. 12, pp. 1808–1814, 2002.

[102] J. F. McDyer, M. N. Hackley, T. E. Walsh, J. L. Cook, andR. A. Seder, “Patients with multidrug-resistant tuberculosiswith low CD4+ T cell counts have impaired Th1 responses,”Journal of Immunology, vol. 158, no. 1, pp. 492–500, 1997.

[103] C. E. Gazeta, M. L. S. Santos G, S. H. F. Vendramini, J. M.Pinto Neto, and T. C. S. Villa, “Controle de comunicantesde tuberculose no Brasil: Revisao de literatura (1984–2004),”Revista Latino-Americana de Enfermagem, vol. 16, no. 2, pp.306–313, 2008.

[104] A. Demissie, M. Abebe, A. Aseffa et al., “Healthy individualsthat control a latent infection with Mycobacterium tuber-culosis express high levels of Th1 cytokines and the IL-4antagonist IL-4δ2,” Journal of Immunology, vol. 172, no. 11,pp. 6938–6943, 2004.

[105] A. Demissie, L. Wassie, M. Abebe et al., “The 6-kilodaltonearly secreted antigenic target-responsive, asymptomaticcontacts of tuberculosis patients express elevated levels ofinterleukin-4 and reduced levels of γ interferon,” Infectionand Immunity, vol. 74, no. 5, pp. 2817–2822, 2006.

[106] Y. V. N. Cavalcanti, V. R. A. Pereira, L. C. Reis et al.,“Evaluation of memory immune response to mycobacteriumextract among household contact of tuberculosis cases,”Journal of Clinical Laboratory Analysis, vol. 23, no. 1, pp. 57–62, 2009.

[107] J. O. Olobo, M. Geletu, A. Demissie et al., “Circulating TNF-α, TGF-β, and IL-10 in tuberculosis patients and healthycontacts,” Scandinavian Journal of Immunology, vol. 53, no.1, pp. 85–91, 2001.

[108] S. A. Sharpe, E. Eschelbach, R. J. Basaraba et al., “Determi-nation of lesion volume by MRI and stereology in a macaquemodel of tuberculosis,” Tuberculosis, vol. 89, no. 6, pp. 405–416, 2009.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

roleoftnf-alpha,ifn-gamma,andil-10inthedevelopmentof...

Documents